Nature Genetics
22, 145 - 150 (1999)
doi:10.1038/9649
A polymorphism that affects OCT-1 binding to the TNF promoter
region is associated with severe malariaJulian C. Knight1, Irina Udalova1, Adrian V.S. Hill2, Brian M. Greenwood3, Norbert Peshu4, Kevin Marsh4
& Dominic Kwiatkowski11
Molecular Infectious Diseases Group, Institute of Molecular
Medicine, Oxford OX3 9DS, UK. 2
Molecular Immunology Group, Institute of Molecular
Medicine, Oxford OX3 9DS, UK. 3
Medical Research Council Laboratories, Fajara, The
Gambia and London School of Hygiene and Tropical Medicine, London
WC1E 7HT, UK. 4
Wellcome Clinical Research Unit, Kilifi
, Kenya.
Correspondence should be addressed to Julian C. Knight julian.knight@paediatrics.ox.ac.uk or Dominic Kwiatkowski dominic.kwiatkowski@paediatrics.ox.ac.ukGenetic variation in cytokine promoter regions is postulated to influence
susceptibility to infection, but the molecular mechanisms by which such polymorphisms
might affect gene regulation are unknown. Through systematic DNA footprinting
of the TNF (encoding tumour necrosis factor, TNF) promoter region,
we have identified a single nucleotide polymorphism (SNP) that causes the
helix-turn-helix transcription factor OCT-1 to bind to a novel region of complex
protein-DNA interactions and alters gene expression in human monocytes. The
OCT-1-binding genotype, found in approximately 5% of Africans, is associated
with fourfold increased susceptibility to cerebral malaria in large case-control
studies of West African and East African populations, after correction for
other known TNF polymorphisms and linked HLA alleles.
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